Modulation of phosphate (Pi) and pyrophosphate (PPi) metabolism is critical for development and maintenance of mineralized tissues, including dentin and cementum. Disruption of local Pi/PPi regulators (ANK, PC-1, TNAP) impacts cementogenesis, though dentin formation appears normal, suggesting dentin mineralization is regulated differently than cementum. When factors regulating circulating Pi (FGF-23, PHEX) were disrupted, initial examination indicated that dentin/pulp were affected, while cementum showed minimal disturbance. Based on these data, the following broad hypothesis is set forth: While both cementum and dentin formation are dependent on Pi homeostasis, the genes/proteins controlling formation and regeneration are likely different. We propose that cementogenesis is controlled by ion transporters/local metabolic enzymes including ANK, PC-1, and TNAP, while dentinogenesis is modulated by factors that control levels of circulating Pi, including FGF-23 and PHEX. Aims: Aim 1 will determine the role of ANK, PHEX and FGF-23 during cementogenesis versus root dentinogenesis. Aim 2 will prove that Pi regulation of specific transcription factors controls the cementoblast phenotype. Aim 3 will prove that increasing local levels of Pi at healing sites using fibrin scaffold delivery systems will promote mineralization. Public Health Relevance: These studies will provide critical information about the genes/factors controlling cementum and dentin formation. Ultimately, the knowledge gained will result in improved therapies for treatment of mineralized tissue disorders and diseases, including dental diseases (caries/periodontal disease), hypophosphatemic conditions, ectopic calcification, and osteoporosis, and in new strategies for regeneration of diseased tissues.